Contribution to the study of the mechanism of directed remote-metalation. Evidence for the intermediacy of a geminal dimetallo dialkoxide C(OM) 2 (M = Li, K), first doubly charged director of ortho metalation

Article abstract of DOI:10.1021/ol0474709

(Chemical Equation Presented) The mechanism of the metalation of 2-biphenyl carboxylic acid (1) with the Lochmann-Schlosser superbase was determined by deuteriolysis. Both ortho (C₃) and remote (C_2′) positions are metalated. The C₂-metalated species 2 cyclizes instantaneously. Under suitable conditions, the doubly charged geminal dimetallo dialkoxide group C(OM)₂ 4 directs metalation in the adjacent position (C₁), affording a stable 1-metallo-9H-fluorene-9,9-dimetallo dialkoxide 5 that can be trapped by diverse electrophiles to give 1-substituted 9H-fluoren-9-ones 7 and 9 after acidic workup.

Full text of DOI:10.1021/ol0474709

ORGANIC
LETTERS
2
005
Vol. 7, No. 5
27-830
Contribution to the Study of the
Mechanism of Directed
8
Remote-Metalation. Evidence for the
Intermediacy of a Geminal Dimetallo
Dialkoxide C(OM) (M
Doubly Charged Director of Ortho
Metalation
) Li, K), First
2
†
†,‡
‡
†
David Tilly, Subhendu S. Samanta, Asish De, Anne-Sophie Castanet, and
Jacques Mortier*,
†
UniVersit e´ du Maine and CNRS, Unit e´ de Chimie Organique Mol e´ culaire et
Macromol e´ culaire (UMR 6011), Facult e´ des Sciences, aVenue OliVier Messiaen,
72085 Le Mans Cedex 9, France, and Department of Organic Chemistry,
Indian Association for the CultiVation of Science, 700 032 JadaVpur, Kolkata, India
jacques.mortier@uniV-lemans.fr
Received December 9, 2004
ABSTRACT
The mechanism of the metalation of 2-biphenyl carboxylic acid (1) with the Lochmann
Both ortho (C ) and remote (C ) positions are metalated. The C -metalated species 2 cyclizes instantaneously. Under suitable conditions, the
doubly charged geminal dimetallo dialkoxide group C(OM) 4 directs metalation in the adjacent position (C ), affording a stable 1-metallo-9H-
−Schlosser superbase was determined by deuteriolysis.
3
2′
2′
2
1
fluorene-9,9-dimetallo dialkoxide 5 that can be trapped by diverse electrophiles to give 1-substituted 9H-fluoren-9-ones 7 and 9 after acidic
workup.
3
Although the CO
2
Li group does activate neighboring posi-
We recently communicated that 2-biphenyl carboxylic
1
tions toward metalation, its effect remains fairly weak. This
enables regioflexibility, as most other electronegative sub-
stituents outperform a competing carboxylate group by their
superior ortho-directing power.2
acid (1) readily undergoes metalation in the immediate
vicinity of the carboxylate substituent (C ) when treated with
s-butyllithium (s-BuLi) in THF at -78 °C. A strong
interaction between the highly electron-rich π-system of the
3
†
Universit e´ du Maine and CNRS.
Indian Association for the Cultivation of Science.
‡
(2) Hartung, C. G.; Snieckus, V. Modern Arene Chemistry; Astruc, D.,
Ed.; Wiley-VCH: New York, 2002; p 330.
(3) Tilly, T.; Samanta, S. S.; Faigl, F.; Mortier, J. Tetrahedron Lett. 2002,
43, 8347.
(
1) (a) Gohier, F.; Castanet, A.-S.; Mortier, J. Org. Lett. 2003, 5, 1919.
b) Gohier, F.; Mortier, J. J. Org. Chem. 2003, 68, 2030 and references
therein.
(
1
0.1021/ol0474709 CCC: $30.25
© 2005 American Chemical Society
Published on Web 02/04/2005

Table 1. Metalations of 2-Biphenyl Carboxylic Acid (1)a,b
conditionsc
% 7 (1d1:1d0)
% 1 (3d1:3d0)
d
entry
acid
1
2
1
1
LICKOR (3.5 equiv), benzene, 60 °C, 1 h
(1) LICKOR (3.5 equiv), benzene, 60 °C, 1 h
76 (41:59)
72 (74:26)
10 (20:80)
0
(
2) t-BuLi (2 equiv), 60 °C, 2 h
(1) LICKOR (3.5 equiv), benzene, 60 °C, 1 h
2) n-BuLi (2 equiv), 60 °C, 2 h
3
1
70 (100:0)
0
(
4
5
6
7
1
1
8
8
LICKOR (5 equiv), benzene, 60 °C, 3 h
LICKOR (2 equiv), benzene, 60 °C, 5 h
n-BuLi (2 equiv), Et2O, -78 °C, 2 h
(1) n-BuLi (2 equiv), Et2O, -78 °C, 2 h
60 (100:0)
9 (25:75)
86 (0:100)
90 (60:40)
0
85 (10:90)
0
0
(
2) n-BuLi (3 equiv), Et2O, -78 °C, 2 h
(1) n-BuLi (2 equiv), Et2O, -78 °C, 2 h
2) s-BuLi/TMEDA (3 equiv), Et2O, -78 °C f rt, 2 h
(1) s-BuLi (2.2 equiv), THF, -78 °C, 2 h
2) LICKOR (3.5 equiv), -78 °C, 2 h
8
9
8
1
61 (100:0)
71 (77:23)
0
(
28 (71:29)
(
a
1
b
c
Isotope ratios were determined by H NMR and FIMS. The error is taken to be (5%. Isolated yields (%). Base was allowed to react with the substrate
d
before D2O was added at room temperature. Recovered starting product.
carboxylate and the reagent places s-BuLi in the proximity
of the ortho-carbon, prior to necessarily intramolecular de-
protonation into the ortho position (complex-induced prox-
Scheme 1. Metalation of 2-Biphenyl Carboxylic Acid (1) with
the Lochmann-Schlosser Superbase
4
imity effect (CIPE) process). We now report that 1, by
treatment with the Lochmann-Schlosser superbase (n-
butyllithium/t-BuOK) (LICKOR), affords the fluorenone
skeleton that arises from the metalation of the remote C2′
site. The mechanism is studied by deuteriolysis to identify
the intermediates of the reaction. Strong evidence for the
intermediacy of a geminal dimetallo dialkoxide function
C(OM)
2
(M ) Li, K) as a new director of ortho metalation
is provided.
2-Biphenyl carboxylic acid (1) was submitted to a series
of strong bases under the conditions depicted in Table 1.
Scheme 1 diagrams the manner in which the products are
3
formed. We initially discovered that addition of 1 to 3.5
equiv of preformed LICKOR superbase made of equimo-
lecular amounts of n-butyllithium and potassium tert-
butoxide, followed by acidic hydrolysis (2 M HCl) at room
temperature, produced the fluoren-9-one 7 in 57% yield in
THF at 45 °C and 76% yield in benzene at 60 °C.
6
5
1 (20% 3d , 80% 3d ) (entry 1 and Scheme 1). The
straightforward interpretation of this result is that 7-1d
1
0
1
arises
O,
from exposure of a stable trianion 5 (M ) Li or K) to D
2
is formed via the tetrahedral dialkoxide 4.7
,8
whereas 7-1d
The trianion 5 arises either from metalation of 4 directed by
the gem-dimetallo dialkoxide group [C(OM) ] (path A) or,
0
Treatment of 1 (100% d
h at 60 °C in benzene, followed by quench with an excess
of D O at room temperature, provided the fluorenone 7 (41%
, 59% 1d ) in 76% yield after separation from unreacted
0
) with 3.5 equiv of LICKOR for
1
2
2
more unlikely, from the cyclization of the trianion 6 formed
1d
1
0
(
4) (a) Beak, P.; Meyers, A. I. Acc. Chem. Res. 1986, 19, 356. (b) Whisler,
M. N.; MacNeil, S.; Snieckus, V.; Beak, P. Angew. Chem, Int. Ed. 2004,
3, 2206.
5) For recent reviews on reaction of organolithium compounds with
(6) Although it is generally admitted that LICKOR needs to be handled
below -50 °C because of the rapid decomposition of the solvent (usually
THF), this result shows that it is not necessarily the case if the base reacts
faster with the substrate than with the solvent.
4
(
1
alkali metal alkoxides and reactions of superbases, see: (a) Lochmann, L.
(7) H NMR spectrum of the residue in THF-d8 displays broad signals
Eur. J. Inorg. Chem. 2000, 1115. (b) Schlosser, M. Eur. J. Org. Chem.
with poor resolution in the aromatic region that are probably due to the
presence of aggregates that prevent a simple structural elucidation.
2
001, 3975.
828
Org. Lett., Vol. 7, No. 5, 2005

by metalation of 2 at the remote C2′ site (path B). The
organometallic species 2 and 3 are formed by metalation,
necessarily irreversible, of 1 by the superbase in positions
Scheme 2. Formation of Fluorenones 7-1d
0 1
and 7-1d from 8
by a Bromine-Lithium Exchange Reaction
3
C and C2′, respectively. The carboxylate group of 3 acts as
an in situ trap for the arylanion thus formed, and the system
cyclizes to give the dialkoxide 4. 2 has a sufficient lifetime
2 1
to be quenched by D O to give 1-3d .
To demonstrate that the trianion 5 is formed by metalation
of 4 directed by the gem-dialkoxide group rather than by
cyclization of 6, the following experiments have been done.
After introduction of LICKOR (3.5 equiv) at 60 °C into a
benzene solution containing the acid 1, 2 equiv of t-BuLi
°
C f rt) followed by D
exclusively (86%, entry 6) (Scheme 2). Since 2′-deuterio-
-biphenyl carboxylic acid (1-2′d ) was not detected under
2 0
O afforded unlabeled 7 (100% d )
2
was further added (entry 2). A quench by D O provided the
2
1
fluorenone 7 containing 74% deuterium incorporation (72%).
When n-BuLi (2 equiv) and LICKOR (5 equiv) were allowed
to react under the conditions depicted (entries 3 and 4),
these conditions, the dianion 3 is unstable and cyclizes
instantaneously to give the dilithio gem-dialkoxide 4 (M )
Li).
13
1 1
isotopically pure 7-d (100% d ) was produced.
We note that the control experiments carried out with 8
may not be perfect mimics of the DreM reaction carried out
with the LICKOR superbase. The organometallic species that
is produced from 2-biphenyl carboxylic acid (1) and the
LICKOR superbase could be part of aggregates that could
have different reactivity than exogenous lithium 2′-lithio
biphenyl carboxylate (3) obtained from 2′-bromobiphenyl
carboxylic acid (8) by bromine-lithium exchange.
From the distribution products obtained (run 5) with 2
equiv of LICKOR, it can be deduced that the directing ortho
metalation (DoM) of 4 leading to 5 (path A) is competitive
in rate with the initial directed remote-metalation (DreM)
of the acid 1 leading to 7. This result explains why 3 equiv
of LICKOR at least is required for optimal conversion of 1
to 7.
The nature of the cations M involved in the stable
organometallic species 4 and 5 is not known with certainty.
In the literature, gem-dialkoxides were reported to be much
more stable when the counterions were lithium rather than
The fluorenone arises from exposure of 4 to aqueous
acid. Treatment of the species dilithio gem-dialkoxide 4
14
with 3 equiv of n-BuLi (-78 °C f rt) followed by D
gave 7 in a yield of 90% (60% d , 40% d ) via the trianion
(M ) Li, entry 7). It is noteworthy that, when the same
reaction was performed with the 1:1 complex s-BuLi/
TMEDA (3 equiv), isotopically pure 7-1d was obtained
61%, entry 8).
2
O,
1
0
2 2
potassium. Whereas Ph C(OLi) can be heated for hours in
5
9
refluxing ether without an appreciable decomposition, the
corresponding dipotassium salt (or the incipient salt) is an
intermediate in the cleavage of benzophenone by potassium
1
(
1
0
t-butoxide to give phenylpotassium and potassium benzoate.
Remarkably, the ortho-lithio benzoate 2 (M ) Li),
11
From the fact that C
6 5
H K
is also present in the mixture,
prepared by treatment of 1 with s-BuLi in THF at -78 °C3
the structure of the organometallic species might be more
complex than observed in the case of metalations carried
out in THF or hydrocarbons with the LICKOR superbase
itself. Both the structure of superbases in solution and the
nature of the actual reactive species have been the objects
of controversial discussions.12
is stable over hours in THF at room temperature and does
15
not give autocondensation products. Treatment of the
preformed dianion 2 with LICKOR (3.5 equiv) (-78 °C f
rt) (entry 9) led to 7 in 71% yield (77% deuterium
incorporation), and 1 was recovered in both deuterated and
1 0
nondeuterated forms (71% 3d , 29% 3d ). An equilibrium
Bromine-lithium exchange by treatment of 2′-bromobi-
phenyl carboxylic (8) with n-BuLi (2 equiv) in ether (-78
between 2 and 3 most probably occurs via an intermolecular
path as already observed in the sulfonate case. Accordingly,
16
deprotonation of 1 with LICKOR is not site-selective.
Since the formation of 2 is a nonissue, cyclization of 3
leading to 4 is fast and irreversible and the equilibrium 2 h
3 is shifted toward the formation of 3 by Le Ch aˆ telier’s
Principle. Whereas 2 is stable at room temperature, a fast Li
h K permutation presumably allows the equilibrium 2 (M
(
8) Dialkoxide 4 is not trappable by electrophiles: treatment of the species
4
with iodomethane or dimethyl sulfate gave the fluorenone 7 even when
hydrolysis of the reaction mixture with water was omitted. The replacement
of one atom of metal (M ) Li or K) by an alkyl group gave an unstable
salt C(OM)(OR) that lost alkoxide ion before a second substitution occurred
to produce a ketal. See: (a) Bluhm, H. F.; Donn, H. V.; Zook, H. D. J.
Am. Chem. Soc. 1955, 77, 4406. These results are consistent with the
findings of the reaction of the diethyl amide corresponding to 1: (b) Fu,
J.-m. Ph.D. Thesis, University of Waterloo, 1990.
)
K) h 3 to be effective.
(
9) (a) Hodge, P.; Perry, G. M.; Yates, P. J. Chem. Soc., Perkin Trans.
Under the optimized one-pot procedure found (entry 3,
Table 1), trianion 5 was trapped with diverse electrophiles
1
1
1977, 680. (b) Bluhn, H. F.; Donn, H. V.; Zook, H. D. J. Am. Chem. Soc.
955, 77, 4406.
(
10) (a) Rawson, G.; Wynberg, H. Recl. TraV. Chim. Pays-Bas 1971,
9
0, 46. (b) Gassman, P. G.; Lumb, J. T.; Zalar, F. V. J. Am. Chem. Soc.
(13) Filler, R.; Fiebig, A. E.; Pelister, M. Y. J. Org. Chem. 1980, 45,
1
967, 89, 946. (c) Davies, D. G.; Derenberg, M.; Hodge, P. J. Chem. Soc.
1290.
C 1971, 455.
(14) Reaction of the isolated fluorenone 7 with LICKOR (3.5 equiv) in
benzene at 60 °C led to the 1,2-addition product 9-butyl-9H-fluoren-9-ol
(75%).
(11) (a) Lochmann, L. Collect. Czech. Chem. Commun. 1987, 52, 2710.
(b) Schlosser, M.; Choi, J. H.; Takagishi, S. Tetrahedron 1990, 46, 5633.
(
12) (a) Bauer, W.; Lochmann, L. J. Am. Chem. Soc. 1992, 114, 7482.
b) Kremer, T.; Harder, S.; Junge, M.; Schleyer, P. v. R. Organometallics
996, 15, 585.
(15) Parham, W. E.; Sayed, Y. A. J. Org. Chem. 1974, 39, 2051.
(16) Alo, B. I.; Familoni, O. B. J. Chem. Soc., Perkin Trans. 1 1990,
1611.
(
1
Org. Lett., Vol. 7, No. 5, 2005
829

others on the mechanism of directed remote-metalations that
19
are followed by intramolecular trapping. Our results suggest
that delivery of the alkyllithium by prior coordination to the
chelating atom assists a metalation that takes place in a
nonregiospecific fashion. Evidence for the intermediacy of
Scheme 3. Synthesis of 1-Substituted Fluorenones 9a-d
a geminal dimetallo dialkoxide C(OM) (M ) Li, K), the
2
first doubly charged director of ortho metalation, is also
provided. Extensions of the manipulation of other gem-
dimetallo dialkoxides are ongoing in our laboratories and
will be reported upon in due course.
(
C
2
Cl
fluorenones 9a-d.
previous research by Snieckus, Qu e´ guiner, Mongin, and
6
, C
2
Br
2
Cl
4
, I
2
7,18
, Me
2
S
2
) to give the corresponding
1
Acknowledgment. This research was supported by the
CNRS, Universit e´ du Maine, and Institut Universitaire de
France.
This work complements and extends
(
17) General Procedure. n-Butyllithium (4.5 mL, 7.8 mmol) was added
to a suspension of potassium tert-butoxide (792 mg, 7.07 mmol) in benzene
10 mL) at ambient temperature. After the mixture was stirred for 5 min,
Supporting Information Available: Details of compound
characterization. This material is available free of charge via
the Internet at http://pubs.acs.org.
(
LICKOR was transferred into a round flask containing 2-biphenyl carboxylic
acid (1) (400 mg, 2.02 mmol) in benzene (5 mL). Stirring was maintained
for 1 h at 60 °C, and the temperature was allowed to cool to room
temperature. n-Butyllithium (2.5 mL, 4.05 mmol) was added dropwise, and
the mixture was stirred at 60 °C for an additional 2 h. After the reaction
mixture was warmed to room temperature gradually, the reaction was
quenched with the electrophile (40.4 mmol) in benzene (6 mL). Standard
workup provided the desired fluorenone, which was purified by chroma-
tography on silica gel (cyclohexane/ethyl acetate 90:10).
OL0474709
(19) These include, inter alia, reactions of 2-, 3-, and 4-pyridylben-
zoates: (a) Rebstock, A.-S.; Mongin, F.; Tr e´ court, F.; Qu e´ guiner, G.
Tetrahedron 2003, 59, 4973. 2-Biphenyl diethylamide: (b) Fu, J.-M.; Zhao,
B.-P.; Sharp, M. J.; Snieckus, V. J. Org. Chem. 1991, 56, 1683. (c) Fu,
J.-m.; Snieckus, V. Can. J. Chem. 2000, 78, 905. (d) Wang, W.; Snieckus,
V. J. Org. Chem. 1992, 57, 424. 2-Aminobiphenyl: (e) Narasimhan, N. S.;
Alurhar, R. H. Indian J. Chem. 1969, 7, 1280. (f) Narasimhan, N. S.;
Chandrachood, P. S. Synthesis 1979, 589. (g) Narasimhan, N. S.; Chan-
drachood, P. S.; Shete, N. R. Tetrahedron 1981, 37, 825. 1-(2′-Carboxy-
phenyl)pyrrole: (h) Cartoon, M. E. K.; Cheeseman, G. W. H. J. Organomet.
Chem. 1981, 212, 1.
(
18) (Trimethylsilyl)-9H-fluoren-9-one that is produced by trapping the
intermediate with chlorotrimethylsilane is not stable under these conditions.
The silyl group is presumably metalated. See inter alia: (a) Wang, G.;
Snieckus, V. J. Org. Chem. 1992, 57, 424. (b) Brough, P. A.; Fisher, S.;
Zhao, B.-P.; Thomas, R. C.; Snieckus, V. Tetrahedron Lett. 1996, 37, 2915.
c) Mohri, S.-I.; Stefinovic, M.; Snieckus, V. J. Org. Chem. 1997, 62, 7072
and references therein.
(
830
Org. Lett., Vol. 7, No. 5, 2005